tbuckley/cabot-search huggingface dataset:
Genetic studies of paired metabolomes reveal enzymatic and transport processes at the interface of plasma and urine
Authors: Pascal Schlosser, Nora Scherer, Franziska Grundner-Culemann, Sara Monteiro-Martins, Stefan Haug, Inga Steinbrenner, Burulça Uluvar, Matthias Wuttke, Yurong Cheng, Arif B. Ekici, Gergely Gyimesi, Edward D. Karoly, Fruzsina Kotsis, Johanna Mielke, Maria F. Gomez, Bing Yu, Morgan E. Grams, Josef Coresh, Eric Boerwinkle, Michael Köttgen, Florian Kronenberg, Heike Meiselbach, Robert P. Mohney, Shreeram Akilesh, Miriam Schmidts, Matthias A. Hediger, Ulla T. Schultheiss, Kai-Uwe Eckardt, Peter J. Oefner, Peggy Sekula, Yong Li, Anna Köttgen
Journal: Nature Genetics (2023)

Abstract The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 ( SLC13A3 ) and ASBT ( SLC10A2 ). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.
Psychedelics promote plasticity by directly binding to BDNF receptor TrkB
Authors: Rafael Moliner, Mykhailo Girych, Cecilia A. Brunello, Vera Kovaleva, Caroline Biojone, Giray Enkavi, Lina Antenucci, Erik F. Kot, Sergey A. Goncharuk, Katja Kaurinkoski, Mirjami Kuutti, Senem M. Fred, Lauri V. Elsilä, Sven Sakson, Cecilia Cannarozzo, Cassiano R. A. F. Diniz, Nina Seiffert, Anna Rubiolo, Hele Haapaniemi, Elsa Meshi, Elina Nagaeva, Tiina Öhman, Tomasz Róg, Esko Kankuri, Marçal Vilar, Markku Varjosalo, Esa R. Korpi, Perttu Permi, Konstantin S. Mineev, Mart Saarma, Ilpo Vattulainen, Plinio C. Casarotto, Eero Castrén
Journal: Nature Neuroscience (2023)

Abstract Psychedelics produce fast and persistent antidepressant effects and induce neuroplasticity resembling the effects of clinically approved antidepressants. We recently reported that pharmacologically diverse antidepressants, including fluoxetine and ketamine, act by binding to TrkB, the receptor for BDNF. Here we show that lysergic acid diethylamide (LSD) and psilocin directly bind to TrkB with affinities 1,000-fold higher than those for other antidepressants, and that psychedelics and antidepressants bind to distinct but partially overlapping sites within the transmembrane domain of TrkB dimers. The effects of psychedelics on neurotrophic signaling, plasticity and antidepressant-like behavior in mice depend on TrkB binding and promotion of endogenous BDNF signaling but are independent of serotonin 2A receptor (5-HT 2A ) activation, whereas LSD-induced head twitching is dependent on 5-HT 2A and independent of TrkB binding. Our data confirm TrkB as a common primary target for antidepressants and suggest that high-affinity TrkB positive allosteric modulators lacking 5-HT 2A activity may retain the antidepressant potential of psychedelics without hallucinogenic effects.
Amino acid metabolism in immune cells: essential regulators of the effector functions, and promising opportunities to enhance cancer immunotherapy
Authors: Luming Yang, Zhaole Chu, Meng Liu, Qiang Zou, Jinyang Li, Qin Liu, Yazhou Wang, Tao Wang, Junyu Xiang, Bin Wang
Journal: Journal of Hematology & Oncology (2023)

Abstract Amino acids are basic nutrients for immune cells during organ development, tissue homeostasis, and the immune response. Regarding metabolic reprogramming in the tumor microenvironment, dysregulation of amino acid consumption in immune cells is an important underlying mechanism leading to impaired anti-tumor immunity. Emerging studies have revealed that altered amino acid metabolism is tightly linked to tumor outgrowth, metastasis, and therapeutic resistance through governing the fate of various immune cells. During these processes, the concentration of free amino acids, their membrane bound transporters, key metabolic enzymes, and sensors such as mTOR and GCN2 play critical roles in controlling immune cell differentiation and function. As such, anti-cancer immune responses could be enhanced by supplement of specific essential amino acids, or targeting the metabolic enzymes or their sensors, thereby developing novel adjuvant immune therapeutic modalities. To further dissect metabolic regulation of anti-tumor immunity, this review summarizes the regulatory mechanisms governing reprogramming of amino acid metabolism and their effects on the phenotypes and functions of tumor-infiltrating immune cells to propose novel approaches that could be exploited to rewire amino acid metabolism and enhance cancer immunotherapy.
A flexible symbolic regression method for constructing interpretable clinical prediction models
Authors: William G. La Cava, Paul C. Lee, Imran Ajmal, Xiruo Ding, Priyanka Solanki, Jordana B. Cohen, Jason H. Moore, Daniel S. Herman
Journal: npj Digital Medicine (2023)

Abstract Machine learning (ML) models trained for triggering clinical decision support (CDS) are typically either accurate or interpretable but not both. Scaling CDS to the panoply of clinical use cases while mitigating risks to patients will require many ML models be intuitively interpretable for clinicians. To this end, we adapted a symbolic regression method, coined the feature engineering automation tool (FEAT), to train concise and accurate models from high-dimensional electronic health record (EHR) data. We first present an in-depth application of FEAT to classify hypertension, hypertension with unexplained hypokalemia, and apparent treatment-resistant hypertension (aTRH) using EHR data for 1200 subjects receiving longitudinal care in a large healthcare system. FEAT models trained to predict phenotypes adjudicated by chart review had equivalent or higher discriminative performance ( p &lt; 0.001) and were at least three times smaller ( p &lt; 1 × 10 −6 ) than other potentially interpretable models. For aTRH, FEAT generated a six-feature, highly discriminative (positive predictive value = 0.70, sensitivity = 0.62), and clinically intuitive model. To assess the generalizability of the approach, we tested FEAT on 25 benchmark clinical phenotyping tasks using the MIMIC-III critical care database. Under comparable dimensionality constraints, FEAT’s models exhibited higher area under the receiver-operating curve scores than penalized linear models across tasks ( p &lt; 6 × 10 −6 ). In summary, FEAT can train EHR prediction models that are both intuitively interpretable and accurate, which should facilitate safe and effective scaling of ML-triggered CDS to the panoply of potential clinical use cases and healthcare practices.
Platelets and mast cells promote pathogenic eosinophil recruitment during invasive fungal infection via the 5-HIAA-GPR35 ligand-receptor system
Authors: Marco De Giovanni, Eric V. Dang, Kevin Y. Chen, Jinping An, Hiten D. Madhani, Jason G. Cyster
Journal: Immunity (2023)

Cryptococcus neoformans is the leading cause of fungal meningitis and is characterized by pathogenic eosinophil accumulation in the context of type-2 inflammation. The chemoattractant receptor GPR35 is expressed by granulocytes and promotes their migration to the inflammatory mediator 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. Given the inflammatory nature of cryptococcal infection, we examined the role of GPR35 in the circuitry underlying cell recruitment to the lung. GPR35 deficiency dampened eosinophil recruitment and fungal growth, whereas overexpression promoted eosinophil homing to airways and fungal replication. Activated platelets and mast cells were the sources of GPR35 ligand activity and pharmacological inhibition of serotonin conversion to 5-HIAA, or genetic deficiency in 5-HIAA production by platelets and mast cells resulted in more efficient clearance of Cryptococcus. Thus, the 5-HIAA-GPR35 axis is an eosinophil chemoattractant receptor system that modulates the clearance of a lethal fungal pathogen, with implications for the use of serotonin metabolism inhibitors in the treatment of fungal infections.
Triplication of the interferon receptor locus contributes to hallmarks of Down syndrome in a mouse model
Authors: Katherine A. Waugh, Ross Minter, Jessica Baxter, Congwu Chi, Matthew D. Galbraith, Kathryn D. Tuttle, Neetha P. Eduthan, Kohl T. Kinning, Zdenek Andrysik, Paula Araya, Hannah Dougherty, Lauren N. Dunn, Michael Ludwig, Kyndal A. Schade, Dayna Tracy, Keith P. Smith, Ross E. Granrath, Nicolas Busquet, Santosh Khanal, Ryan D. Anderson, Liza L. Cox, Belinda Enriquez Estrada, Angela L. Rachubinski, Hannah R. Lyford, Eleanor C. Britton, Katherine A. Fantauzzo, David J. Orlicky, Jennifer L. Matsuda, Kunhua Song, Timothy C. Cox, Kelly D. Sullivan, Joaquin M. Espinosa
Journal: Nature Genetics (2023)

Abstract Down syndrome (DS), the genetic condition caused by trisomy 21, is characterized by variable cognitive impairment, immune dysregulation, dysmorphogenesis and increased prevalence of diverse co-occurring conditions. The mechanisms by which trisomy 21 causes these effects remain largely unknown. We demonstrate that triplication of the interferon receptor ( IFNR ) gene cluster on chromosome 21 is necessary for multiple phenotypes in a mouse model of DS. Whole-blood transcriptome analysis demonstrated that IFNR overexpression associates with chronic interferon hyperactivity and inflammation in people with DS. To define the contribution of this locus to DS phenotypes, we used genome editing to correct its copy number in a mouse model of DS, which normalized antiviral responses, prevented heart malformations, ameliorated developmental delays, improved cognition and attenuated craniofacial anomalies. Triplication of the Ifnr locus modulates hallmarks of DS in mice, suggesting that trisomy 21 elicits an interferonopathy potentially amenable to therapeutic intervention.
Preventing mental illness in children that experienced maltreatment the efficacy of REThink online therapeutic game
Authors: Oana A. David, Liviu A. Fodor
Journal: npj Digital Medicine (2023)

Exposure to child maltreatment (CM) is considered to predispose children to devastating consequences in terms of mental health. Thus, it is a public health priority to provide these children with early preventive interventions that are accessible on a large scale, adapted to their needs, and effective in supporting their mental health. Here we report a randomized control trial to test the efficacy of the REThink online therapeutic game, as compared with a Care as Usual (CAU) control group in the prevention of mental illness in maltreated children. Out of 439 children aged 8-12 that were recruited, 294 children with self-reported maltreatment histories were included in the current study, and were allocated, 146 participants in the REThink group and 148 participants in the CAU group. All children completed pre- and post-intervention assessments measuring mental health, emotion regulation, and irrational cognitions. We also tested potential moderators for these effects, such as the severity of CM and the security of parent attachment. Our results show that children receiving the REThink game intervention outperform the CAU group at post-test, showing a significantly lower level of emotional problems, mental health difficulties, use of maladaptive emotion-regulation strategies such as catastrophizing, rumination, and self-blame, and irrational cognitions. Moreover, children with higher CM severity benefit the most from the REThink game, while children with lower parent attachment security benefit the least. Future research is needed, to investigate the long-term efficacy of the REThink game in promoting the mental health of children exposed to CM.
Mechanistic insights into the interactions between cancer drivers and the tumour immune microenvironment
Authors: Hrvoje Misetic, Mohamed Reda Keddar, Jean-Pierre Jeannon, Francesca D. Ciccarelli
Journal: Genome Medicine (2023)

Abstract Background The crosstalk between cancer and the tumour immune microenvironment (TIME) has attracted significant interest in the latest years because of its impact on cancer evolution and response to treatment. Despite this, cancer-specific tumour-TIME interactions and their mechanistic insights are still poorly understood. Methods Here, we compute the significant interactions occurring between cancer-specific genetic drivers and five anti- and pro-tumour TIME features in 32 cancer types using Lasso regularised ordinal regression. Focusing on head and neck squamous cancer (HNSC), we rebuild the functional networks linking specific TIME driver alterations to the TIME state they associate with. Results The 477 TIME drivers that we identify are multifunctional genes whose alterations are selected early in cancer evolution and recur across and within cancer types. Tumour suppressors and oncogenes have an opposite effect on the TIME and the overall anti-tumour TIME driver burden is predictive of response to immunotherapy. TIME driver alterations predict the immune profiles of HNSC molecular subtypes, and perturbations in keratinization, apoptosis and interferon signalling underpin specific driver-TIME interactions. Conclusions Overall, our study delivers a comprehensive resource of TIME drivers, gives mechanistic insights into their immune-regulatory role, and provides an additional framework for patient prioritisation to immunotherapy. The full list of TIME drivers and associated properties are available at http://www.network-cancer-genes.org .
The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets
Authors: Kimberley El, Jonathan D. Douros, Francis S. Willard, Aaron Novikoff, Ashot Sargsyan, Diego Perez-Tilve, David B. Wainscott, Bin Yang, Alex Chen, Donald Wothe, Callum Coupland, Mattias H. Tschöp, Brian Finan, David A. D’Alessio, Kyle W. Sloop, Timo D. Müller, Jonathan E. Campbell
Journal: Nature Metabolism (2023)

Abstract The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance 1 . The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity 2 , whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity 3,4 . However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control 5 . Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.
<i>NLRC5</i>germline variants as potential pharmacogenomic markers for immune checkpoint inhibitors
Authors: Xiang-Yu Meng
Journal: Journal for ImmunoTherapy of Cancer (2023)

I read with interest the recent report by Caulfield et al . In this elegant piece of work, the authors performed RNA-seq and whole exome sequencing (WES) on tumors from a small cohort of subjects that presented insulin-dependent diabetes after treatment by immune checkpoint inhibitors (ICIs), which
Simple Hysterectomy Safe for Some Cervical Cancers
Journal: Cancer Discovery (2023)

Abstract Findings from the SHAPE trial confirm that carefully selected women with early-stage cervical cancer can undergo a simple hysterectomy instead of a radical procedure without increasing their risk of disease recurrence. The findings are likely to set a new global standard of care for patients with low-risk disease and help to improve outcomes in developing countries, where deaths from cervical cancer are highest.
Reduced mitochondrial calcium uptake in macrophages is a major driver of inflammaging
Authors: Philip V. Seegren, Logan R. Harper, Taylor K. Downs, Xiao-Yu Zhao, Shivapriya B. Viswanathan, Marta E. Stremska, Rachel J. Olson, Joel Kennedy, Sarah E. Ewald, Pankaj Kumar, Bimal N. Desai
Journal: Nature Aging (2023)

Mitochondrial dysfunction is linked to age-associated inflammation or inflammaging, but underlying mechanisms are not understood. Analyses of 700 human blood transcriptomes revealed clear signs of age-associated low-grade inflammation. Among changes in mitochondrial components, we found that the expression of mitochondrial calcium uniporter (MCU) and its regulatory subunit MICU1, genes central to mitochondrial Ca2+ (mCa2+) signaling, correlated inversely with age. Indeed, mCa2+ uptake capacity of mouse macrophages decreased significantly with age. We show that in both human and mouse macrophages, reduced mCa2+ uptake amplifies cytosolic Ca2+ oscillations and potentiates downstream nuclear factor kappa B activation, which is central to inflammation. Our findings pinpoint the mitochondrial calcium uniporter complex as a keystone molecular apparatus that links age-related changes in mitochondrial physiology to systemic macrophage-mediated age-associated inflammation. The findings raise the exciting possibility that restoring mCa2+ uptake capacity in tissue-resident macrophages may decrease inflammaging of specific organs and alleviate age-associated conditions such as neurodegenerative and cardiometabolic diseases.
150 risk variants for diverticular disease of intestine prioritize cell types and enable polygenic prediction of disease susceptibility
Authors: Yeda Wu, Slavina B. Goleva, Lindsay B. Breidenbach, Minsoo Kim, Stuart MacGregor, Michael J. Gandal, Lea K. Davis, Naomi R. Wray
Journal: Cell Genomics (2023)

We conducted a genome-wide association study (GWAS) analysis of diverticular disease (DivD) of intestine within 724,372 individuals and identified 150 independent genome-wide significant DNA variants. Integration of the GWAS results with human gut single-cell RNA sequencing data implicated gut myocyte, mesothelial and stromal cells, and enteric neurons and glia in DivD development. Ninety-five genes were prioritized based on multiple lines of evidence, including SLC9A3, a drug target gene of tenapanor used for the treatment of the constipation subtype of irritable bowel syndrome. A DivD polygenic score (PGS) enables effective risk prediction (area under the curve [AUC], 0.688; 95% confidence interval [CI], 0.645-0.732) and the top 20% PGS was associated with ∼3.6-fold increased DivD risk relative to the remaining population. Our statistical and bioinformatic analyses suggest that the mechanism of DivD is through colon structure, gut motility, gastrointestinal mucus, and ionic homeostasis. Our analyses reinforce the link between gastrointestinal disorders and the enteric nervous system through genetics.
Remote Monitoring for Heart Failure Management at Home
Authors: Lynne Warner Stevenson, Heather J. Ross, Lisa D. Rathman, John P. Boehmer
Journal: Journal of the American College of Cardiology (2023)

Early telemonitoring of weights and symptoms did not decrease heart failure hospitalizations but helped identify steps toward effective monitoring programs. A signal that is accurate and actionable with response kinetics for early re-assessment is required for the treatment of patients at high risk, while signal specifications differ for surveillance of low-risk patients. Tracking of congestion with cardiac filling pressures or lung water content has shown most impact to decrease hospitalizations, while multiparameter scores from implanted rhythm devices have identified patients at increased risk. Algorithms require better personalization of signal thresholds and interventions. The COVID-19 epidemic accelerated transition to remote care away from clinics, preparing for new digital health care platforms to accommodate multiple technologies and empower patients. Addressing inequities will require bridging the digital divide and the deep gap in access to HF care teams, who will not be replaced by technology but by care teams who can embrace it.
Immunotherapies targeting GPRC5D in relapsed or refractory multiple myeloma: latest updates from 2022 ASH Annual Meeting
Authors: Jieyun Xia, Zhenyu Li, Kailin Xu
Journal: Journal of Hematology & Oncology (2023)

Abstract B cell maturation antigen (BCMA)-targeted immunotherapy has shown unprecedented results in the treatment of relapsed or refractory (R/R) multiple myeloma (MM). However, disease progression remains an issue attributed to variable BCMA expression, BCMA downregulation, and heterogeneity of tumor antigens in MM. Therefore, additional treatment options with novel therapeutic targets are warranted. G protein-coupled receptor, class C group 5 member D (GPRC5D), an orphan receptor expressed on malignant plasma cells with limited expression in normal tissue, has emerged as a promising therapeutic target for R/R MM. GPRC5D-targeted chimeric antigen receptor (CAR)-T and CAR-NK cell therapy, as well as bispecific T cell engagers, offer remarkable anti-tumor activities. We summarized some latest reports on GPRC5D-targeted treatments for R/R MM from the 2022 ASH Annual Meeting (ASH 2022).
Emerging roles of oligodendrocyte precursor cells in neural circuit development and remodeling
Authors: JoAnn Buchanan, Nuno Maçarico da Costa, Lucas Cheadle
Journal: Trends in Neurosciences (2023)

Oligodendrocyte precursor cells (OPCs) are non-neuronal brain cells that give rise to oligodendrocytes, glia that myelinate the axons of neurons in the brain. Classically known for their contributions to myelination via oligodendrogenesis, OPCs are increasingly appreciated to play diverse roles in the nervous system, ranging from blood vessel formation to antigen presentation. Here, we review emerging literature suggesting that OPCs may be essential for the establishment and remodeling of neural circuits in the developing and adult brain via mechanisms that are distinct from the production of oligodendrocytes. We discuss the specialized features of OPCs that position these cells to integrate activity-dependent and molecular cues to shape brain wiring. Finally, we place OPCs within the context of a growing field focused on understanding the importance of communication between neurons and glia in the contexts of both health and disease.
Potential herb–drug interactions between anti-COVID-19 drugs and traditional Chinese medicine
Authors: Ling Ye, Shicheng Fan, Pengfei Zhao, Chenghua Wu, Menghua Liu, Shuang Hu, Peng Wang, Hongyu Wang, Huichang Bi
Journal: Acta Pharmaceutica Sinica B (2023)

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has spread worldwide. Effective treatments against COVID-19 remain urgently in need although vaccination significantly reduces the incidence, hospitalization, and mortality. At present, antiviral drugs including Nirmatrelvir/Ritonavir (Paxlovid
Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase γ-subunit
Authors: Iwan C. Meij, Jan B. Koenderink, Hans van Bokhoven, Karin F.H. Assink, Wouter Tiel Groenestege, Jan Joep H.H.M. de Pont, René J.M. Bindels, Leo A.H. Monnens, Lambert P.W.J. van den Heuvel, Nine V.A.M. Knoers
Journal: Nature Genetics (2000)